Addition of Modulators of Homocysteine to Adalimumab Therapy in the Treatment of Moderate to Severe Plaque Psoriasis

A Single-Center, Open-Label Study to Assess the Effects of the Addition of Modulators of Homocysteine to Adalimumab Therapy in the Treatment of Moderate to Severe Plaque Psoriasis Evaluated With the PASI, PGA and DLQI

Vitamins modulating homocysteine affect both TNF-alpha, vascular endothelial growth factor, and theoretically enhance the anti-inflammatory version of NOS thus hopefully increasing the efficacy and reducing the chance of some toxicities of adalimumab as determined by blood testing and EKGs.

Study Overview

• Status: Terminated
• Conditions: Psoriasis
• Intervention / Treatment: Drug: Humira Then Humira plus 3 B vitamins

Detailed Description

This is a pilot study designed to evaluate whether addition of oral vitamin B12, vitamin B6, and folic acid to the use of adalimumab for psoriasis leads to further improvement of a patient's psoriasis and quality of life.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• adults 18 or older
• moderate to severe plaque psoriasis (>10% BSA)
• Negative pregnancy test within 7 days before first dose of adalimumab in all women (except surgically sterile or 5 years postmenopausal)
• subject must sign/date appropriate written informed consent&HIPAA authorization
• Sexually active subjects of childbearing potential must agree to use medically acceptable contraception during screening and throughout the study
• no evidence of active or latent tuberculosis based on a negative PPD skin test performed at screening, or within one year of starting this study. Patients with documentation of adequately treated TB may be enrolled
• Patients PPD positive and CXR negative can be enrolled if they finish appropriate INH prophylaxis prior to enrollment
• be willing and able to self-administer subcutaneous injections or to have a qualified person available to administer these injections
• agrees to comply with protocol requirements, attend all regularly study visits and is considered to be a good study subject
• meets concomitant medication washout requirements
• willing to use only allowed psoriasis medications and treatments and agree not to start any topical, systemic, or phototherapy for psoriasis during the study period
• adalimumab naïve

Exclusion Criteria:

• erythrodermic, pustular, or guttate psoriasis
• skin conditions other than psoriasis that would interfere with study-related psoriasis evaluations
• known sensitivity to any component of the study medications
• Evidence of active infections such as fevers, chills, sweats, or history of untreated Lyme disease and active severe infections within 4 weeks before screening visit, or between the screening and Week 0 visits
• history of listeriosis, untreated TB, persistent or active infections requiring hospitalization or treatment with IV antibiotics, IV antiretrovirals, or IV antifungals within 30 days of baseline, OR oral antibiotics, antivirals, or antifungals for purpose of treating infection, within 14 days of baseline
• positive PPD and positive chest x-ray for latent or active tuberculosis
• positive PPD and negative chest x-ray that have not completed appropriate INH prophylaxis
• On immune compromising drug or history of immune compromising disorder or immunodeficiency
• poorly controlled medical condition including, not limited to, unstable cardiovascular disease, poorly controlled diabetes, recent stroke, history of recurrent infections, or any condition for which, in the opinion of the investigators, participation in the study would place the subject at risk
• hx. congestive heart failure
• hx. demyelinating CNS disease
• History of malignancy (other than previously treated localized carcinoma in situ of the cervix or previously treated nonmelanoma skin cancer)
• history of or ongoing drug or alcohol abuse
• past or present psychiatric morbidity which may compromise the study
• Pregnant women, nursing mothers, or planning to become pregnant during study or within 150 days after last dose of study medication. Males planning pregnancy with spouse/partner while in study are to be excluded
• plans to receive any live vaccines during study
• history of liver disease
• Current enrollment in another clinical study/treatment with other experimental drug or approved therapy for experimental use within 30 days prior to Week 0
• previous enrollment in this study
• cannot commit to all assessments required by the protocol
• disorder that compromises the subject to give written informed consent and/or comply with study procedures
• considered by the investigators to be unsuitable candidate
• cannot comply with the protocol washout requirements
• on folic acid in doses over than the minimal daily requirements
• on vitamins higher than minimal daily requirements (multivitamins are allowed)
• colon polyps or cancer
• prior adalimumab therapy
• on screening plasma Vascular Endothelial Growth Factor level is 140 pg/ml or more

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Humira then Humira plus 3 B vitamins; Humira then Humira plus 3 B vitamins The only arm: After 16 weeks on adalimumab, modulators of homocysteine (oral vitamin B12, oral vitamin B6 or pyridoxine, and oral folic acid) will be added to adalimumab therapy for an additional 12 weeks. At end of this therapy can stop or continue. Telephone call day 70 after formal end of in person study the investigators will assess general health of each subject.

Drug: Humira Then Humira plus 3 B vitamins; Humira alone for 16 weeks then Humira plus 100 mg daily pyridoxine, 5 mg daily folic acid and 1000 mcg daily cyanocobalamin; Other Names: Cyanocobalamin; Vitamin B9; Humira; Adalimumab; Vitamin B12; Vitamin B6; Pyridoxine; Folic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Particpants With a Categorical PASI (Psoriasis Area and Severity Index) Change	PASI: formula based on body surface areas on head/neck, trunk, both arms & legs with disease quality grading induration, scale and erythema on participants ages 18-65 with moderate to severe plaque psoriasis measured at weeks 16 and 28.	Weeks 16 and 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With a Categorical Change in Static Physician Global Assessment (sPGA):	Number of participants with a category change in Physician static Global Assessment (sPGA): 7 point score from 0 (clear) to 6 measuring amount of surface covered and plaque qualities: thickness & erythema plus scaling. Dynamic score compares baseline with either improvement/ worsening of the same factors measured in the sPGA using the 0-6 scoring range but focused on change. sPGA at weeks 16 AND 28. dynamic PGA to be categoically measured at.weeks16 and 28.	Week 16 and Week 28
Number of Participants With a Categorical DLQI (Dermatology Life Quality Index) Change	DLQI is 10 questions examining impact of skin disease on quality of life: (1) symptoms & feelings (2) daily activities (3) leisure (4) work & school (5) personal relationship (6) treatment. To be administered to adults over 18 years with moderate to severe plaque psoriasis at week 0 (no systemic psoriasis medication);. weeks 16 ( after 16 weeks of adalimumab) and week 28 (after 16 weeks adalimumab then 12 weeks of adalimumab plus daily 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg B12).	Week 16 and Week 28
Number of Participants With Category Change in Serum VEGF (Vascular Endothelial Growth Factorl)	Adult particpants ages 18 or older with moderate to severe plaque psoriasis were to have serum VEGF measured at week 0 on no systemic psoriasis medication then at both weeks 16 on adalimumab and at week 28 on adalimumab plus folic acid, B6 and Vitamin B12. Subjects raniked by BMI week 0 low to high	At Screening visit, Week 16 on Humira, after another 12 weeks on Humira plus vitamins and if early termination
Number of Participants Within the Categories of Increasing and Decreasing Serum Homocysteine	Serum homocysteine measured at week 16 after 16 weeks of adalimumab and week 28 after 16 weeks of adalimumaband then 12 weeks of adalimumab plus 5 mg folic acid, 100mg B6 and 1000 mcg of B12 in adults ages 18-65 with moderate to sever plaque psoriasis..	Week 16 and Week 28
Number of Participants With Category Change in Vitamin B12 Blood Level	Adult participants 18 years or older with moderate to severe plaque psoriasis were to have serum B12 levels measures Weeks 0 (on no systemic psoriasis medication), 16 (on adalimumab) and week 28 (on adalimumab plus daily 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg B12.	At Week 16 and Week 28
Number of Participants Within the Categories of Increasing and Decreasing Serum Vitamin B6 Level	Serum vitamin B6 levels were to be measured weeks16 after 16 weeks adalimumab and at week 28 after 16 weeks adalimumab and 12 weeks on adalimuamb, folic acid 5 mg, b6 100 mg and B12 1000 mcg in adult participants with moderate to sever plque psoriasis.	At Week 16 and Week 28
Number of Participants With Category Change in Serum Folic Acid Level.	Serum folic acid level in adults ages 18 and older with mild to moderate plaque psoriasis measured at week 16 after 16 weeks adalimumab and at week 28 after 16 weeks adalimumab plus 12 weeks of adalimumab and daily 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg B12.	Weeks 16 and 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants in the Categories of Having and Not Having an Adverse Event	Worsening psoriasis or development or worsening of measured condition or new pathology not seen by week 16 but developed at weeks 28 or first discoved by telephone call day 70 post study: AE Humira only	After Week 16 of study
Number of Participants in the Categories of Having and of Not Having a Serious Adverse Event (SAE)	A serious adverse event is hosptalization or death or pathology leading to early termination of a participant from the study. This was to be reported at anytime during the 28 week study of adult patients ages 18-65 with moderate to severe plaque psoriasis though categorized by Week 16 (on adalimumab alone, by Week 28 (on adalimuamb plus 3 B vitaminsand by day 70 post Week 28.	By Week 16, by Week 28 and by Day 70 post Week 28.
Number of Participants in the Categories of Normalizing, Unchanging and Newly Abnormal Electrocardiograms (EKGs)	An electrocardiogram (EKG) is used to evaluate the electrical activity of the heart by converting this activity into line tracings on paper.. Electrodes (small, plastic patches) are placed at certain locations on the chest, arms, and legs. When the electrodes are connected to an EKG machine by lead wires, the electrical activity of the heart is measured, interpreted, and printed out for the doctor's information and further interpretation. This test was to be administered to adults age 18 or older with moderate to severe plaque psoriasis patients at week 0, 16 and week 28 of this study.	Week 16 and then Week 28 after another 12 weeks on Humira plus vitamins and if early termination
Number of Participants in Categories or Increasing and Decreasing Changes Within the CBC (Complete Blood Count)	Change in CBC parameter: white blood count or hemoglobin or hematocrit ( as measured week 16 on adalimumab and at week 28 after 12 more weeks on adalimuamb , folic acid, B6 and B12) in adults ages 18-65 with moderate to severe plaque psoriasis.	Week 16 and Week 28
Number of Participants Within the Categories of Increasing and Decreasing Serum Magnesium	Serum magnesium (Mg) was to be measured at baseline, Week 16 (on adalimumab) and at week 28 (on adalimumab plus folic acid, vitamins B6 and B12) in adult participants age 18 or older with moderate to severe plaque psoriasis.	Weeks 16 and 28
Number of Participants Within the Categories of Increasing and Decreasing Serum Phosphorus	Serum phosphorus (P) levels were to be measured weeks16 and 28 in adult participants age 18 and older with moderate to severe plaque psoriasis at week 0 on no systemic psoriasis medication; week 16 after 16 weeks of adalimumab and at week 28 after 16 weeks of adalimumab plus 12 weeks of adalimumab plus 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg of B12.	Week 16 then Week 28
Number of Participants Within the Categories of Elevated and Normal Helicobacter Pylori Antibody	Adult participants age 18 years or older with moderate to severe plaque psoriasis with serum IgG antibodies against Helicobacter pylori bacteria using commercial ELISA assay during the 28 week study.	Week 28 after 16 weeks of Adalimumab then 12 of Adalimumab-Vitamins
Number of Participants Within the Categories of Positive Urine Pregnancy Test (Urine Hcg)	Women of childbearing years over age 18 with moderate to severe plaque psoriasis on no systemic therapy at week 0 of study.	At screening
Number of Participants Within the Categories of Increasing and Decreasing Blood Pressure and Pulse Measures:	Blood pressure is the force the heart exerts against the walls of arteries as it pumps the blood out to the body. The unit of measurement is millimeters of mercury (mm Hg). Pulse is the number of times your heart beats per minute. The unit of measurement is beats per minute (BPM). These test measurements compared in adults with moderate to severe plaque psoriasis week 16 after 16 weeks adalimumab and week 28 after 16 weeks adalimumab plus 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg vitamin B12.	Week 16 and Week 28
Number of Participants Within Categories of Body Temperature Change	Using a thermometer for body temperature on degrees Fahrenheit. Participants to be measured were adults 18 years or older with moderate to severe plaque psoriasis with temperature to be measured at week 16 16 weeks of adalimumab and week 28 after 16 weeks of adalimumab then 12 weeks of adalimumab plus 5 mg folic acid, 100 mg vitamin B6 and 1000 mcg of B12.	Weeks 16 and 28
Number of Participants Who Fulfilled the Category of Having Height Measured	Height is the distance from the bottom (soles of feet ) to the top (top of head) of a person when that person is standing in this study using ruler in inches.Participants measured were adults age 18 or older with moderate to severe plaque psoriasis.	Week 0 at Start of Adalimumab
Number of Participants Within the Categories of Increasign and Decreasing Body Weight	Weight is how heavy a participant is. Weight in pounds of each study adult participant age 18-65 years with moderate to severe plaque psoriasis measured at weeks 16 and compared to week 28 of study.	Week 16 and Week 28

Collaborators and Investigators

• Sponsor: Wayne State University
• Collaborators: Abbott
• Investigators: Principal Investigator: Peter J Aronson, MD, Department Dermatology Wayne State University

Publications and helpful links

General Publications

• Lewis V, Finlay AY. 10 years experience of the Dermatology Life Quality Index (DLQI). J Investig Dermatol Symp Proc. 2004 Mar;9(2):169-80. doi: 10.1111/j.1087-0024.2004.09113.x. No abstract available.
• Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington (DC): National Academies Press (US); 1998. Available from http://www.ncbi.nlm.nih.gov/books/NBK114310/
• Aronson PJ, Malick F. Towards rational treatment of severe psoriasis in alcoholics: report of two cases. J Drugs Dermatol. 2010 Apr;9(4):405-8.
• Moat SJ, Madhavan A, Taylor SY, Payne N, Allen RH, Stabler SP, Goodfellow J, McDowell IF, Lewis MJ, Lang D. High- but not low-dose folic acid improves endothelial function in coronary artery disease. Eur J Clin Invest. 2006 Dec;36(12):850-9. doi: 10.1111/j.1365-2362.2006.01739.x.
• Li W, Zheng T, Wang J, Altura BT, Altura BM. Extracellular magnesium regulates effects of vitamin B6, B12 and folate on homocysteinemia-induced depletion of intracellular free magnesium ions in canine cerebral vascular smooth muscle cells: possible relationship to [Ca2+]i, atherogenesis and stroke. Neurosci Lett. 1999 Oct 22;274(2):83-6. doi: 10.1016/s0304-3940(99)00683-7.
• Gordon KB, Langley RG, Leonardi C, Toth D, Menter MA, Kang S, Heffernan M, Miller B, Hamlin R, Lim L, Zhong J, Hoffman R, Okun MM. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J Am Acad Dermatol. 2006 Oct;55(4):598-606. doi: 10.1016/j.jaad.2006.05.027. Epub 2006 Aug 10.
• Genovese MC, Mease PJ, Thomson GT, Kivitz AJ, Perdok RJ, Weinberg MA, Medich J, Sasso EH; M02-570 Study Group. Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy. J Rheumatol. 2007 May;34(5):1040-50. Epub 2007 Apr 15. Erratum In: J Rheumatol. 2007 Jun;34(6):1439.
• Pitarch G, Sanchez-Carazo JL, Mahiques L, Perez-Ferriols MA, Fortea JM. Treatment of psoriasis with adalimumab. Clin Exp Dermatol. 2007 Jan;32(1):18-22. doi: 10.1111/j.1365-2230.2006.02288.x.
• Leonardi C, Langley RG, Papp K, Tyring SK, Wasel N, Vender R, Unnebrink K, Gupta SR, Valdecantos WC, Bagel J. Adalimumab for treatment of moderate to severe chronic plaque psoriasis of the hands and feet: efficacy and safety results from REACH, a randomized, placebo-controlled, double-blind trial. Arch Dermatol. 2011 Apr;147(4):429-36. doi: 10.1001/archdermatol.2010.384. Epub 2010 Dec 20.
• Stuart PE, Nair RP, Ellinghaus E, Ding J, Tejasvi T, Gudjonsson JE, Li Y, Weidinger S, Eberlein B, Gieger C, Wichmann HE, Kunz M, Ike R, Krueger GG, Bowcock AM, Mrowietz U, Lim HW, Voorhees JJ, Abecasis GR, Weichenthal M, Franke A, Rahman P, Gladman DD, Elder JT. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet. 2010 Nov;42(11):1000-4. doi: 10.1038/ng.693. Epub 2010 Oct 17.
• Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, Krueger JG. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol. 2011 Feb;131(2):391-400. doi: 10.1038/jid.2010.280. Epub 2010 Sep 23.

Helpful Links

• Search for Humira
• hypermagnesemia

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: October 3, 2012
• First Submitted That Met QC Criteria: October 9, 2012
• First Posted (Estimate): October 11, 2012

Study Record Updates

• Last Update Posted (Estimate): February 4, 2015
• Last Update Submitted That Met QC Criteria: January 30, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Psoriasis; Vitamin B12; Folic acid; Vitamin B6; B vitamins; Adalimumab; Homocysteine; Cyanocobalamin; Pyridoxine; Vitamin B9
• Additional Relevant MeSH Terms: Skin Diseases; Skin Diseases, Papulosquamous; Psoriasis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Micronutrients; Hematinics; Adalimumab; Vitamins; Folic Acid; Vitamin B 12; Vitamin B Complex; Vitamin B 6; Pyridoxine
• Other Study ID Numbers: Dermatology 1104009591